Impaired Cholesterol Metabolism and Enhanced Atherosclerosis in Clock Mutant Mice

Article

关键词: INTESTINAL LIPID ABSORPTION;    CIRCADIAN CLOCK;    DIURNAL REGULATION;    ABCA1 GENE;    HYPERLIPIDEMIA;    TRIGLYCERIDE;    TRANSPORT;    PROMOTER;    CELLS;   

DOI  :  10.1161/CIRCULATIONAHA.113.002885

来源: SCIE

【 摘 要 】

Background Clock is a key transcription factor that positively controls circadian regulation. However, its role in plasma cholesterol homeostasis and atherosclerosis has not been studied. Methods and Results We show for the first time that dominant-negative Clock mutant protein (Clock(19/19)) enhances plasma cholesterol and atherosclerosis in 3 different mouse models. Detailed analyses revealed that Clk(19/19)Apoe(-/-) mice display hypercholesterolemia resulting from the accumulation of apolipoprotein B48-containing cholesteryl ester-rich lipoproteins. Physiological studies showed that enhanced cholesterol absorption by the intestine contributes to hypercholesterolemia. Molecular studies indicated that the expression of Niemann Pick C1 Like 1, Acyl-CoA:Cholesterol acyltransferase 1, and microsomal triglyceride transfer protein in the intestines of Clk(19/19)Apoe(-/-) mice was high and that enterocytes assembled and secreted more chylomicrons. Furthermore, we identified macrophage dysfunction as another potential cause of increased atherosclerosis in Clk(19/19)Apoe(-/-) mice. Macrophages from Clk(19/19)Apoe(-/-) mice expressed higher levels of scavenger receptors and took up more modified lipoproteins compared with Apoe(-/-) mice, but they expressed low levels of ATP binding casette protein family A member 1 and were defective in cholesterol efflux. Molecular studies revealed that Clock regulates ATP binding casette protein family A member 1 expression in macrophages by modulating upstream transcription factor 2 expression. Conclusions Clock(19/19) protein enhances atherosclerosis by increasing intestinal cholesterol absorption, augmenting uptake of modified lipoproteins by macrophages, and reducing cholesterol efflux from macrophages. These studies establish that circadian Clock activity is crucial in maintaining low plasma cholesterol levels and in reducing atherogenesis in mice.

【 授权许可】

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